Iodixanol, trade name Visipaque®, was developed by Nycomed as a non-ionic X-ray contrast agent. Iodixanol was introduced in 1993, and is manufactured in large quantities.
The production of this non-ionic X-ray contrast agent includes chemical manufacturing (primary production) and the manufacture of pharmaceutical preparations (secondary production); the primary production of iodixanol includes a multi-step chemical synthesis and is completed by a purification process.
Iodixanol for injection is directly injected into human blood vessels at very high dosages, which means that a very high quality for the iodixanol used as the raw material in secondary production is required. Hence the purity of the iodixanol should conveniently be even higher than that of the United States Pharmacopoeia standards. Notwithstanding, the efficiency and economy of primary production of commercial pharmaceutical products is equally important. Hence improvements in the chemical synthesis and the purification process of iodixanol is very important.
The chemical synthesis and the purification process of iodixanol can be both independent and associated with each other.
The literature cites in recent years many ways to prepare iodixanol. These include multi-step chemical synthesis as well as chromatographic and non-chromatographic purification methods. The cost of the final product available in the Pharmacy has largely been dependent on these processes, hence it is important to optimize these processes from the viewpoint of economic effectiveness and environmental protection.
A. Synthesis of Iodixanol
All of the major chemical synthetic processes known for the preparation of iodixanol start with 5-nitroisophthalic acid. The first reported method was described in EP 0108638 wherein the final intermediate 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (hereinafter referred to as compound A) is reacted with a reagent such as epichlorohydrin or 1,3-dichloro-2-hydroxyl propane to form iodixanol (hereinafter this reaction is referred to as dimerization). See Scheme 1.

The total yield of this process is relatively low and the purification process of the final product, iodixanol, is very expensive and time consuming. The purification processes described in EP 0108638 include the use of preparative liquid chromatography to carry out the purification. At the same time, the low purity of the product prepared by the method described also increases the difficulty of its purification. The use of preparative liquid chromatography makes it difficult to produce the product economically and efficiently in an industrial process. Production of large quantities is difficult.
Attempts have been made to find efficient and economical methods to prepare iodixanol. Priebe published an article (Acta Radioi. 36 (1995), Suppl 399, 21-31) attempting to increase the yield of the chemical synthesis. This article describes an alternative route to avoid difficulties in the dimerization shown in Scheme 1. However, this route involves eight reaction steps from 5-nitroisophthalic acid, one step includes a chlorination with thionyl chloride, which is a strongly corrosive. Also, the iodine atoms are introduced early in the synthetic route, which is disadvantageous as iodine is the most expensive regent in the process thus giving restricted opportunities to reduce the costs. The yield and final purification method of this route have not yet been reported.
The third synthetic route to prepare iodixanol prepares 5-amino-2,4,6-triiodo-isophthalic acid (WO 96/37458), which is then converted to its acid dichloride (WO 96/37459) then to compound A (U.S. Pat. No. 5,705,692) and finally dimerization carried out according to the process of Scheme 1. The difference between these two processes is that they use different routes to synthesis compound A. Hence this method has the same defects as the first synthesis process along with the undesirable acid chlorination step.
A fourth method to prepare iodixanol has been reported in KR 0050006367A and KR 050024944A. Compound A is firstly reacted with hydroxyl-protection reagent, then dimerization, and finally a de-protection step is carried out to prepare the iodixanol. This has two more reaction steps, but no increase of yield was reported although a reduction of O-alkylation was observed.
B. Purification Process of Iodixanol
a). Chromatographic Purification Methods
EP 108638 describes the use of preparative liquid chromatography to carry out the purification. The use of RP-HPLC applied to a solution containing non-ionic compounds to decolorize, separate and purify contrast agents which are water-soluble and non-ionic are described in Mallinckrodt Inc.'s EP 0470247B1. Bracco S.p.A's EP 0902686B1 describes a refined purification method for contrast agents, including the joint application of chromatography and nanofiltration technology. Chromatography and nanofiltration is used on the crude solution to carry out the separations and then ion-exchange resin to carry out the decolourization.
Iodixanol can be purified to medicinal acceptable purity by any of the above-mentioned methods, which use preparative chromatography. The largest deficiency of these methods is that the cost of process may be increased and that the requirements for large scale manufactured cannot be met.
b). Non-Chromatographic Purification Methods
Several attempts to find alternative methods of purification to avoid liquid chromatographic methods described in EP 0108636.
WO 99/18054 describes a process for the crystallization of iodixanol where the crystallization is carried out using a high energy process, specifically under elevated pressure and at a temperature above the boiling point of the solution at atmospheric pressure.
WO 00/47549 describes a process to prepare iodixanol. Unreacted compound A may precipitate out from the reaction mixture, and recovered for reuse in the next batch thus increasing the total yield of the process. When most of the unreacted compound A is precipitated out from the reaction mixture, traditional crystallization, instead of high performance liquid chromatography, can be applied.
When iodixanol is crystallized from a mixture of methanol and 2-propanol (WO 9918054) with a small amount of residual water under reflux, the crystallization is slow and the purification effect is limited. To achieve the desired purity, the iodixanol crude product coming directly from the synthesis is crystallized twice. The process is time consuming and takes about 3 days for the first crystallization and about 2 days for the second.
WO 2006/016815 describes a method of purification by crystallization from 1-methoxy-2-propanol and water. WO 2007/064220 describes a method of purification by crystallization from a solution in ethanol and water. WO 2007/073202 describes a method of crystallization by using various solvents. In this method n-propanol or iso-propanol and water as purification solvents is described. However, the process is even more time consuming taking about three days and giving a yield of about 80-85%.
In CN 101293855A a large amount of polar solvents such as 2-methoxyethanol, ethanol and methanol are used to dissolve crude product. Then a small amount of a less polar solvent such as methyl acetate, ethyl acetate, acetonitrile are added to the solution until turbidity occurs. After slow cooling and crystallization iodixanol of increased purity is obtained.
This method needs to be repeated five times, and the total yield is only 30% or less. These methods do not have the high-performance and economy of preparation required and are difficult to reproduce on an industrial scale.
To sum up, a purity of iodixanol by HPLC of 75-90% is required before purification by crystallisation can be applied. However, the purity of the crude material from the synthetic sequence is generally 50-60%. Hence, it is necessary to improve the process to prepare iodixanol. The process of the chemical synthesis undoubtedly limits any improvement in the efficiency of the purification and the quality of the product.